Category Archives: HRT

Low-Dose Estrogen Increases Bone Density in Postmenopausal Women


Effects of a low-dose oral estrogen only treatment on bone mineral density and quantitative ultrasonometry in postmenopausal women.

The aim of this study was to evaluate an oral low-dose estrogen therapy on bone mineral density (BMD) and quantitative ultrasonometry (QUS) in osteopenic postmenopausal women.
This prospective, open-label cohort study investigated 120 postmenopausal hysterectomized women. Forty-seven women had been treated with 0.3 mg conjugated equine estrogen daily (ET). Primary end point was the change in BMD at the spine after 24 months. Secondary end points were among other changes in QUS at the os calcis and phalanges.
After matching 42 participants in the ET group, 42 controls were analyzed. The change in BMD differed significantly after 24 months (p = 0.019). Women on ET showed significant increase of spine and hip Z-score, whereas controls showed significant decreases in spine and total hip BMD. In QUS of the os calcis and the phalanges, a number of variables showed a significant improvements with ET.
Our results comprised a positive effect of an oral low-dose estrogen therapy on BMD. Limitations of the study are the small sample size and the open-label, non-randomized cohort study design. The findings are in accordance to the common literature and support the use of ET in the primary prevention of postmenopausal bone loss.

Ziller M, Herwig J, Ziller V, Kauka A…
Gynecol. Endocrinol. Dec 2012
PMID: 22835159

Review: New Treatments


New developments in the treatment of osteoporosis.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.

Eriksen EF, Halse J, Moen MH
Acta Obstet Gynecol Scand Jun 2013
PMID: 22646526

Melatonin Implants Influence Bone Repair in Rabbits


Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae.

The pineal gland hormone, melatonin, is an immunomodulator and neuroendocrine hormone; it also stimulates monocyte, cytokine and fibroblast proliferations, which influence angiogenesis. The aim of this study was to investigate the effects of melatonin on angiogenesis during bone defect repair by means of radiological and histomorphometric evaluations of bone response to melatonin implants.
Twenty New Zealand rabbits weighing 3,900-4,500 g were used. Twenty melatonin implants were inserted in the proximal metaphyseal area of the animals’ right tibia and 20 control areas were located in the left proximal metaphyseal area. Following implantation, the animals were sacrificed in groups of five, after 1, 2, 3 and 4 weeks, respectively. Anteroposterior and lateral radiographs were taken, and radiographic thermal imaging analysis was performed for all groups at different time stages following implant insertion. Samples were sectioned at 5 μm and stained using Hematoxylin-Eosin and Masson’s trichrome, supplementing radiographic findings with histomorphometric analysis.
After 4 weeks, radiological images showed complete repair of the bone defects. No healed or residual bone alterations attributable to the presence of the melatonin implant were observed. Histomorphometric analysis at 4 weeks showed the presence of a higher density newly formed bone. There were statistically significant differences in the length of cortical formation between the melatonin group and the control group during the first weeks of the study; there were also statistically significant differences in the number of vessels observed in the melatonin groups at the first two study stages.
Melatonin may have potential beneficial effects on bone defect repair.

Ramírez-Fernández MP, Calvo-Guirado JL, de-Val JE, Delgado-Ruiz RA…
Clin Oral Investig Jan 2013
PMID: 22323056

Melatonin Induces Bone Sialoprotein In Vitro


Melatonin regulates human bone sialoprotein gene transcription.

Melatonin is produced by the pineal gland and regulates various physiological processes including osteoblast differentiation and bone formation. Bone sialoprotein (BSP) is a mineralized connective tissue-specific protein expressed in the early stage of cementum and bone mineralization. To elucidate the effects of melatonin on human BSP gene expression, we utilized human Saos2 osteoblast-like cells. Melatonin (100 nM) increased the level of BSP mRNA at 3 h, and the level became maximal at 12 and 24 h. We then investigated the melatonin-induced transcriptional activity of luciferase constructs (between -84LUC and -868LUC) including different lengths of the human BSP gene promoter transfected into Saos2 cells. The effects of melatonin abrogated in constructs included 2-bp mutations in the two cAMP response elements (CRE1 and CRE2). The effects of melatonin were suppressed by protein kinase A, tyrosine kinase, ERK1/2 and phosphatidylinositol 3-kinase inhibitors. Gel mobility shift assays showed that melatonin increased the binding of nuclear proteins to CRE1 and CRE2, and antibodies against CRE binding protein 1 (CREB1), phospho-CREB1, c-Fos, c-Jun, JunD and Fra2 disrupted CRE1 and CRE2 protein complex formation. These data indicate that melatonin induces BSP transcription via the CRE1 and CRE2 elements in the human BSP gene promoter.

Matsumura H, Ogata Y
J Oral Sci 2014
PMID: 24739710 | Free Full Text

Melatonin Benefits Bones in Old Rats


Melatonin dietary supplement as an anti-aging therapy for age-related bone loss.

Introduction: Previous studies have shown that melatonin, an antioxidant molecule secreted from the pineal gland, is a positive regulator of bone mass. However, melatonin potential effects on bone mass have never been investigated in old population yet. The aim of this study was to assess the effects of dietary melatonin supplementation on mass accrual and biomechanical properties of old rat femora. Methods: Twenty 22-months-old male Wistar rats were divided into 2 randomly assigned groups. The first group was treated for 10 weeks with melatonin, whereas the second group left untreated (control). Rat femurs were collected, and their phenotypes and biomechanical properties were investigated by micro-computed tomography, histomorphometry and 3-point-bending test. Statistical analyses were performed by Student’s two-tailed unpaired t-test. In all experiments, a value of p < 0.05 was considered significant. Results: Rats treated with melatonin had higher bone volume, bone trabecular number, trabecular thickness and cortical thickness in comparison to control group. Histomorphometric analyses confirmed the increase of bone volume in melatonin-treated rats. In agreement with these findings, melatonin-treated rats demonstrated with higher bone stiffness, flexural modulus and ultimate load compared to controls. Conclusion: These compelling results are the first evidence indicating that dietary melatonin supplementation is able to exert beneficial effects against age-related bone loss in old rats; improving the microstructure and biomechanical properties of aged bones.

Tresguerres IF, Tamimi F, Eimar H, Barralet J…
Rejuvenation Res Mar 2014
PMID: 24617902

Review: Melatonin Induces Osteoblastogenesis and Inhibits Osteoclastogenesis


Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures.

An important role for melatonin in bone formation and restructuring has emerged, and studies demonstrate the multiple mechanisms for these beneficial actions. Statistical analysis shows that even with existing osteoporotic therapies, bone-related disease, and mortality are on the rise, creating a huge financial burden for societies worldwide. These findings suggest that novel alternatives need to be developed to either prevent or reverse bone loss to combat osteoporosis-related fractures. The focus of this review describes melatonin’s role in bone physiology and discusses how disruption of melatonin rhythms by light exposure at night, shift work, and disease can adversely impact on bone. The signal transduction mechanisms underlying osteoblast and osteoclast differentiation and coupling with one another are discussed with a focus on how melatonin, through the regulation of RANKL and osteoprotegerin synthesis and release from osteoblasts, can induce osteoblastogenesis while inhibiting osteoclastogenesis. Also, melatonin’s free-radical scavenging and antioxidant properties of this indoleamine are discussed as yet an additional mechanism by which melatonin can maintain one’s bone health, especially oral health. The clinical use for melatonin in bone-grafting procedures, in reversing bone loss due to osteopenia and osteoporosis, and in managing periodontal disease is discussed.

Maria S, Witt-Enderby PA
J. Pineal Res. Dec 2013
PMID: 24372640

Hypothesis: Melatonin for Osteoporosis


Is postmenopausal osteoporosis related to pineal gland functions?

There is currently considerable interest in the pathogenesis of postmenopausal osteoporosis, which is the most common metabolic bone disease. Osteoporosis affects approximately 20 million persons in the United States, 90% of whom are postmenopausal women. Although there is evidence that estrogen deficiency is an important contributory factor, the pathogenesis of osteoporosis is multifactorial and presently poorly understood. There is evidence that pineal melatonin is an anti-aging hormone and that the menopause is associated with a substantial decline in melatonin secretion and an increased rate of pineal calcification. Animal data indicate that pineal melatonin is involved in the regulation of calcium and phosphorus metabolism by stimulating the activity of the parathyroid glands and by inhibiting calcitonin release and inhibiting prostaglandin synthesis. Hence, the pineal gland may function as a “fine tuner” of calcium homeostasis. In the following communication, we propose that the fall of melatonin plasma levels during the early stage of menopause may be an important contributory factor in the development of postmenopausal osteoporosis. Consequently, plasma melatonin levels taken in the early menopause could be used as an indicator or perhaps as a marker for susceptibility to postmenopausal osteoporosis. Moreover, light therapy, administration of oral melatonin (2.5 mg at night) or agents which induce a sustained release of melatonin secretion such as 5-methoxypsoralen, could be useful agents in the prophylaxis and treatment of postmenopausal osteoporosis. Finally, since application of external artificial magnetic fields has been shown to synchronize melatonin secretion in experimental animals and humans, we propose that treatment with artificial magnetic fields may be beneficial for postmenopausal osteoporosis.

Sandyk R, Anastasiadis PG, Anninos PA, Tsagas N
Int. J. Neurosci. Feb 1992
PMID: 1305608

Garlic < Lovastatin < Estrogen Effective in suppressing Bone loss in Ovariectomized Rats


Effects of garlic oil on postmenopausal osteoporosis using ovariectomized rats: comparison with the effects of lovastatin and 17beta-estradiol.

The purpose of this study was to examine the antiosteoporosis effects of garlic oil in an ovariectomized (Ovx) rat model of osteoporosis and to compare its efficacy with lovastatin (a synthetic hypocholesterolemic drug) and 17beta-estradiol (a potent antiosteoporotic agent). Animals were divided into five groups: sham-operated control, ovariectomized, ovariectomized supplemented with lovastatin, ovariectomized supplemented with garlic oil and ovariectomized supplemented with 17beta-estradiol. In our study, the development of a high rate of bone turnover and osteoporosis in the ovariectomized animals were confirmed by significant alterations of serum alkaline phosphatase activity, serum tartrate-resistant acid phosphatase activity, urinary excretion of calcium, phosphate, hydroxyproline and urinary calcium to creatinine ratio, when compared with the sham-operated control group. Supplementation of these animals with either garlic oil or lovastatin or 17beta-estradiol, in addition to their hypocholesterolemic effect, could counterbalance all these changes. The results revealed that all three compounds significantly protected the hypogonadal bone loss as reflected by higher bone densities and higher bone mineral contents than the ovariectomized group of animals. The results emphasize that, like 17beta-estradiol, the hypocholesterolemic compounds garlic oil and lovastatin are also effective in suppressing bone loss owing to estrogen deficiency and their efficacy in the order of lower to higher is garlic < lovastatin < 17beta-estradiol.

Mukherjee M, Das AS, Das D, Mukherjee S…
Phytother Res Jan 2006
PMID: 16397916

Risedronate, Atorvastatin, Estrogen, Raloxifene, and Clomiphene Compared in Ovariectomized Rats


Comparative effects of risedronate, atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats.

The aim of this study was to investigate bone protective effects of risedronate, atorvastatin, raloxifene and clomiphene citrate in ovariectomized rats.
Our study was conducted on 63 rats at Experimental Research Center of Celal Bayar University. Six-month-old rats were divided into seven groups. There were five drug administered ovariectomized groups, one ovariectomized control group without drug administration and one non-ovariectomized control group without drug administration. Eight weeks postovariectomy, rats were treated with the bisphosphonate risedronate sodium, the statin atorvastatin, the estrogen 17beta-estradiol and the selective estrogen receptor modulators (SERMs) raloxifene hydrochloride and clomiphene citrate by gavage daily for 8 weeks. At the end of the study, rats were killed under anesthesia. For densitometric evaluation, left femurs and tibiae were removed. Left femurs were also used to measure bone volume. Right femurs were used for three-point bending test.
Compared to ovariectomized group, femur cortex volume increased significantly in non-ovariectomized group (p=0.016). Compared to non-ovariectomized group, distal femoral metaphyseal and femur midshaft bone mineral density values were significantly lower in ovariectomized group (p=0.047). In ovariectomy+atorvastatin group, whole femur and femur midshaft bone mineral density and three-point bending test maximal load values were significantly higher than ovariectomized group (p=0.049, 0.05, and 0.018). When compared to the ovariectomized group, no significant difference was found with respect to femoral maximum load values in groups treated with risedronate, estrogen, raloxifene and clomiphene (p=0.602, 0.602, 0.75, and 0.927). In ovariectomy+risedronate group, femur midshaft bone mineral density values were significantly higher than the values in ovariectomized group (p=0.023). When compared to ovariectomized group, no significant difference was found with respect to femur midshaft bone mineral density values in groups treated with estrogen, raloxifene and clomiphene (p=0.306, 0.808, and 0.095).

While risedronate sodium prevented the decrease in bone mineral density in ovariectomized rats, atorvastatin maintained mechanical characteristics of bone and also prevented the decrease in bone mineral density as risedronate sodium.

Uyar Y, Baytur Y, Inceboz U, Demir BC…
Maturitas Jul 2009
PMID: 19386450

Video: Dr. Hofflich “Osteoporosis Update 2013” – Stein Institute for Research on Aging

Here is a nice talk by Dr. Heather Hofflich from May 15, 2013. She’s an Associate Professor of Medicine at UCSD. She gives an overview of osteoporosis and discusses the causes and therapies used to treat it. She also takes a look at recent controversies in treatment plans and vitamin usage.

One thing that bothers me about her talk is that she claims Teriparatide is the only thing in the world that builds bone by increasing osteoblast activity. I’ve posted many studies that found increases in osteoblasts from a variety of things. She also didn’t mention any other potentially helpful dietary supplements besides Calcium and Vitamin D. Like most MDs, she is probably unaware of anything that is not FDA approved.